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Clinical Cytogenetics (Chapter 5) > Clinical Cytogenetics ch5 > Flashcards

Clinical Cytogenetics ch5 Flashcards

1
Q

Cytogenetics

A

study of chromosomes within a cell

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2
Q

chromosomal abnormalities

A

-can be microscopic–> hard to detect
1 base change can be hard to see
-causes many syndromes
-collectively more than Mendelian single gene disorders

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3
Q

How to look for smaller scale changes in chromosomes? (2)

A

1) PCR: thermocycler–> sequencing= results

2) extract DNA send to a third party and get genome sequenced

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4
Q

Stats on cytogenetic disorders (3) –> Chromosomal abnormalities

A

!) 1% of live births

2) 2% of pregnancies when mom is >35 yrs
3) ~50% of 1st trimester spontaneous abortions

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5
Q

Cytogenetic Testing done in which situations (5)

A

1) mom over 35 yrs
2) growth/developmental delay
3) Still births/neomatal death
4) fertility problems
5) family history
6) neoplasia (cancer)
7) other (keep in mind that others can cause chromosomal abnormalities

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6
Q

cancer

A

uncontrolled cell growth causing a mass of cells

tumour can be benign or metastatic

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7
Q

benign tumour

A

not cancerous; can be removed and doesn’t spread to other parts of the body

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8
Q

malignant tumor

A

can invade tissues and organs

-also metastatic can break off into bloodstream

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9
Q

What materials are used for cytogenetic testing? LIST ONLY (for CGH/PCR) (5)

A

1) T-lymphocytes
2) White blood cells
3) Skin biopsy
4) bone marrow
5) fetal cells

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10
Q

T-lymphocytes

A
  • short term
  • limited number of divisions after extraction
  • need lots of calls
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11
Q

Why do you use metaphase cells instead of interphase cells?

A

because chromosomes are condensed
easier to see
problem could be in cell division

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12
Q

White blood cells

A
  • long term
  • can divide more in lab= longer time to study.
  • can be transformed into lymphoblastoid= cell lines that are potentially immortal
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13
Q

skin biopsy

A

samples of tissue

form fibroblasts that can be used for analysis

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14
Q

bone marrow

A
  • hip bone because biggest bone and can get a big sample

- high proportion of dividing cells

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15
Q

Fetal cells

A

amniotic fluid/

chronic villi sampling–> can be studied directly

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16
Q

How do you distinguish between actual chromosomes?

A

by Size

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17
Q

If two chromosomes are almost the same size (ie 1 and 2) what do you look at to number them?

A

banding

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18
Q

banding patterns

A

characteristic dark and light stained regions

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19
Q

What stage of the cell cycle?

A

metaphase because more condensed easier to manipulate

-different stages= different banding patterns

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20
Q

heterochromatin

A

totally dark regions
genes are off in these regions
`

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21
Q

euchromatin

A

light bands

genes turned on here

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22
Q

G banding

A
  • Giemsa banding
  • G banding shows dark bands in AT rich areas (gene poor areas)
  • promoters, centromeres; weaker regions 2 bonds btw AT vs 3 btw GC = HETEROCHROMATIN
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23
Q

R banding

A

R banding (reverse G banding) shows dark bands in GC rich areas (gene rich areas).

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24
Q

Q banding

A
  • opposite of G banding

- bright Q bands = dark bands of G

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25
Q

C banding and which other type of banding….

A

and Q banding used to detect benign variants with differences in the amount or type of satellite DNA sequences at a certain location on the chromosome

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26
Q

which is the most common type of banding

A

G banding

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27
Q

p arm

A

short arm of a chromosome

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28
Q

q arm

A

long arm of a chromosome

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29
Q

numbering of a chromosome

A

increase from the centromere to the telomere
-centromere to the top
-and centromere to the bottom
(ends being higher in number

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30
Q

banding in prophase

A

longer; more darker bands than in metaphase and different sub-bands

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31
Q

banding in pro-metaphase

A

longer, and more lighter regions than in metaphase and different sub-bands

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32
Q

What can you detect from a standard karyotype?

6

A
  • extra chromosomes
  • deletion
  • chromosome breaks (could lose large portions of chromosomes)
  • translocations/ inversions= large pattern difference
  • gender
  • duplications
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33
Q

F.I.S.H

A

Fluorescence In Situ Hybridization

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34
Q

Technique used to hybridize DNA in FISH

A

1) get sample–> purify DNA
2) lyse cell& nucleus= chromosomes
3) put on a slide so they don’t move
4) denature them (chemically/heat)
5) put in an aqueous liquid to prevent desiccation and store
6) generate a probe –> need to know what we’re looking for and actually making
7) Hybridization (reannealing) probe to sample DNA
8) Microscope

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35
Q

Where to get a probe? (4)

A
  • any piece of DNA in a tube that is cloned into a plasmid
  • chop for a desired length using a restriction enzyme
  • but it; make it by PCR
  • isolate normal individuals DNA–> label that denature it and use it
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36
Q

Why is the signal more intense in the satellite probe?

A

because theres more DNA in a satellite DNA (telomeres/centromeres) than DNA at a locus

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37
Q

different probes with different colours

a) one green; 2 blue; one red
b) three blue; 2 green
c) three red; 1 blue and green

A

a) 46, XY
b) trisomy of chromosome 18 and female
c) trisomy of chromosome 21 and male

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38
Q

Small deletion detection

A
  • FISH
  • portion will be missing
  • doesnt necessarily mean that theres a deletion; the chromosome could be scrambled ie) UV messing with thymine
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39
Q

DeGeorge Syndrome FISH

A

red probe to DNA deleted (22q11.2) supposed to be red dot in each one –> instead only one but control theres 2

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40
Q

FISH CHROMOSOME PAINTING

A

lots of probes from the same chromosome, each is labelled with the same florescent molecule therefore entire chromosome lighting up

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41
Q

Spectral karyotyping

A

-FISH used to paint each chromosome a different colour
-many probes for each chromosome
-Why? because easier for sorting, good for finding translocations (partial colours)
trisomies are clear

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42
Q

Clinical Diagnostic steps (9)

A

1) Patient has disorder–> dont know what it is access phenotypes first
2) Physician makes assessment
3) referral to speciallist
4) assessment of their own
5) family history
6) draw samples/ask physician to send you reports
7) prepare a karyotype (staining)
8) FISH (How to choose probe–> DR. some possibilities of disorders; limited number of probes needed)
9) nothing determined…..(what do we do now–> sequence entire genome –PCR based on phenotype inference

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43
Q

CGH (NAME?)

A

Comparative Genome Hybridization

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44
Q

CGH Definition

A
  • probes that cover the entire ‘normal’ genome (or certain pieces) are fixed to a slide
  • each ‘spot’ corresponds to a specific known position on a chromosome
45
Q

Microarrays

A
  • oligonucleotides (small DNA bits)
  • whole genome on the chip with more than 1 copy
  • label sample DNA–> complementary and read how many DNA bits have hybridized to the chip
46
Q

Hybridize to slide

A
  • small sample (from patient), fragment into small pieces and fluorescently label (red)
  • take normal control DNA, fragment, fluorescently label (green)
  • hybridize both to a slide
47
Q

if quantity is same in patient and control?

A

normal

48
Q

if quantity more in patient than control

A

extra chromosome/s

49
Q

if quantity more in control than patient

A

patient is lacking some chromosomes

50
Q

CGH Array from a computer gives a graph

A

ratio of 1.0=signal is equal to the control
trisomy for an autosome=1.5
monosomy=0.5
male=lower ratio of X; higher ratio for Y
female=higher ratio of X; lower ratio for Y

51
Q

Chromosomal abnormalities

A

-changes in chromosome number (euploidy/aneploidy)
-changes in chromosome structure
(not entire chromosome)

52
Q

what % of first-trimester abortuses are of a abnormal karyotype

A

50%

53
Q

what fraction of mothers >35 are of a abnormal karyotye

A

1/50

54
Q

what fraction of live births are of an abnormal karyotype

A

1/160

55
Q

percentage of numerical abnormalities in first trimester abortuses

A

96%

56
Q

percentage of mothers>35 with numerical abnormalities

A

85%

57
Q

percentage of live births with numerical abnormalities

A

60%

58
Q

Standardized Nomenclature for a deletion

A

46,X_,del (#p/q)

59
Q

Standardized Nomenclature for a derivative

A

(der#)

60
Q

der(1)

A

translocation chromosome derived from chromosome 1 and containing the centromere of chromosome 1

61
Q

Standardized Nomenclature for a duplication (two types)

A

a) fragile site: 46,YorX,fra(X/Y)(p/q##.#)

b) isochromosome: 46,XorY,i(X/Y)(p/q#)

62
Q

Standardized Nomenclature for an inversion

A

inv(#)(p/q#p/q#)

63
Q

Standardized Nomenclature for a translocation

A

46,X_,t(#;#)(p/q#;p/q#)

64
Q

46;XX,del(5p)

A

female with cri du chat syndrome, due to deletion of part of a short arm of one chromosome 5

65
Q

46,Y,fra(X)(q27.3)

A

male with fragile X chromosome (fragile site)

66
Q

46,X,i(X)(q10)

A

female with isochromosomes for the long arm of the X chromosomes

67
Q

inv(3)(p25q21)

A

pericentric inversion of chromosome 3

68
Q

46,XX,t(2;8)(q22;p21)

A

female with balanced translocation between chromosome 2 and chromosome 8, with breaks in 2q22 and 8p21

69
Q

Monosomies are more deleterious than trisomies in live births

A
  • complete monosomies are generally not viable except for monosomy X
  • complete trisomies are viable for chromosomes 13,18,21,X and Y
70
Q

Phenotype in partial aneusomies depends on

A
  • the size of the unbalanced segment
  • whether the imbalance is monosomic or trisomic
  • which regions of the genome are affected and which genes are affected and which genes are involved
71
Q

Mosaicism

A

person has a chromosome abnormality, the abnormality is in all of his/her cells

  • when there are 2 or more different chromosomes that complement
  • can be detected using FISH or CGH
72
Q

inversions are either

A

pericentric or paracentric

an inversion: happens on a single chromosome and breaks in two places the segment btw is inverted (so ABCD into ACBD)

73
Q

pericentric

A
  • the risk of birth defects in offspring increases with the size of an inversion
  • INCLUDES THE THE CENTROMERE
  • BREAK IN EACH ARM
74
Q

paracentric

A

very low risk of abnormal phenotype

  • DOES NOT INCLUDE THE CENTROMERE)
  • BOTH BREAKS HAPPEN IN THE SAME ARM
75
Q

Euploidy

A
  • exact sets of chromosomes
    a) Triploid (3n): 69
    b) Tetraploid (4n): 92 chromosomes –> spontaneous abortions
76
Q

Aneuploidy

A
  • common type of chromosomal disorder
    a) Trisomy: one additional chromosome
  • most but only a few are viable (3,18,21, X&Y)
    b) monosomy: one less chromosome -most lethal except X
  • 1 X= Turner’s Syndrome
77
Q

Why only 13,18 and 21 trisomies?

A
  • less genes than other chromosomes

- trisomic better gene imbalance than chromosome 19 which has many more genes

78
Q

nondisjunction

A
  • mitosis:the failure of sister chromatids to separate during and after mitosis
  • meiosis: failure of homologous chromosomes to separate during and after meiosis
79
Q

Causes of chromosome nondisjunction

A

A) the amount/location of recombination events during M1
-there are either too few or no recombinations
-recombination too close to centromere or telomere
B) premature separation of sister chromatids during M1, instead of M2

80
Q

Abnormalities of chromosome Structure

A

A) less common than aneuploidies (1/375 live births)
B) large-scale rearrangements:
-spontaneous/induced: ionizing radiation/viral infection/chemicals in the environment
-all cells/only a subset of cells are infected:would have happened in the first division of the zygote
-stable/unstable: stable =can be passed on through mitosis; unstable=not
-balanced/unbalanced: loss of material; everything present in proper #; but just shifted around’

81
Q

haploinsufficiency

A

inability of a single copy of the genetic material to carry out the functions of a single copy of the genetic material to carry out the functions normally performed by 2 copies

82
Q

Terminal vs. Interstitial deletions

A

a) loss of the ends
b) interstitial: deletion in the middle of the arm
- terminal more likely than interstitial because terminal only needs one breakpoint; interstitial needs 2 breakpoints

83
Q

deletion

A
  • can occur in recombination

- can detect a deletion by CGH and FISH

84
Q

duplication

A
  • can be caused by unequal crossing-over

- generally less harmful than deletions

85
Q

marker and ring chromosomes

A

-deletions of each end of chromosome and then reattachment

86
Q

isochromsomes

A

-is a chromosome in which one arm is missing and the other is duplicated

87
Q

Balanced Rearrangements

A

inversions and translocation all material is present just mixed up =no loss;no gain

88
Q

Inversions

A 
paracentric= no centromeres
pericentric= includes the centromere
89
Q

How to detect an inversion/translocation?

A

FISH/CGH/Chromosomal staining/PCR followed by sequencing

inversion: large than maybe chromosomal staining and then microscopy. PCR=maybe primers have to face each other= if they dont= fail

translocation: CGH: no loss or gain of material
FISH=YES because probe for the region testing for lightening up on a different chromosome= translocation

90
Q

paracentric inversion heterozygote

A

no centromere; maybe depending on which gene was broken, resulting in a complicated looping. segregating and can break somewhere

-no impact on the individual but could affect the gametes

normal=ABCDE
deletion=ABCD
deletion=A
inversion product= ADCBE

91
Q

common pericentric inversions

A

inv(3)(p25q21)
inv(8)(p23.1q22.1)
inv(9)(p11q12)

92
Q

translocation

A
  • exchange btw the arms of non-homologous chromosomes can be reciprocal/Robertsonian
  • usually harmless for the carrier, can cause unbalanced gametes (due to breakage in a gene)
93
Q

reciprocal translocation

A

type of rearrangement that results from the breakage of non homologous chromosomes with a reciprocal exchange

94
Q

relocation of an oncogene

A

a gene that is not normally expressed is now becomes a housekeeping gene= which is expressed all the time in every gene

95
Q

Robertsonian Translocation

A

-rare (1/1300)
-involves fusion of 2 acrocentric chromosomes
(acrocentric= centromeres at the end= p arm is gene poor
(chromosomes 13,14,15,21,&22)

96
Q

insertion

A
  • non-reciprocal
  • segment from one chromosome is inserted into another; rare because it involves 2 breaks than a 3rd break to move into another chromosome
97
Q

mosaicism

A

a) 2 or more populations of cells in one individual (usually aneuploid rather than structural)
- caused by bone marrow transplant etc..,
- causes: nondisjunction in an early meiotic division
- early= more cells that show an abnormality

98
Q

Parent of Origin Effect

A

for some disorders, which disease phenotype is expressed depends on which parental chromosome is inherited how? genomic imprinting

99
Q

Genomic imprinting

A

specific parts of specific chromosomes become imprinted (or marked) in the germline of one parent but not the other

  • not a change in DNA only modification
  • controls the expression of underlying genes after the formation of the zygote
  • imprinting survives into adulthood
100
Q

epigenetics

A

heritable changes in gene expression/function without changes to DNA sequences

a) DNA methylation
b) histone modification

101
Q

DNA methylation

A

control for gene transcription

102
Q

histone modification

A

acetylation (1 type)–> causes DNA to be compressed= no expression, modified acetylated= DNA available in euchromatin–> histone methylation= heterochromatin

103
Q

Imprinting examples

A

a) Prader-willi Syndrome

b) Angelman Syndrome

104
Q

Prader-willi Syndrome

A 
obesity 
excessive eating
small hands and feet
short stature 
hypogonadism 
mental retardation
105
Q

Angelman Syndrome

A

Unusual facial appearance
short stature
mental retardation
seizures

106
Q

most common cause for both syndromes is the —–deletion

A

15q11-q13

107
Q

if deletion inherited from FATHER

A

prader-willi

108
Q

if deletion inherited from MOTHER

A

Angelman

Clinical Cytogenetics (Chapter 5) (1 decks)

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